DE1593924A1 - Process for the production of substituted guanidines - Google Patents

Description

Priorities ! dated Feb. 28, 1966 under P.7.-Hr./ 51 313 and Nov. 22, 1966 under PV 84 498 in France

The invention relates to a method for producing new Guanidine derivatives, in particular of heterocyclic compounds of g-uanidine. i & lo & »guanidine derivatives are known, and Although ^ Octahydro-2-azooinyl-i-äthylJ -guanidinsulfat of Maxwell and coworkers in Experentia, 15, 267 (1959) and the (Benzodioxaa-i ^ -yl-Sj-methylguanidinsulfat by J. Augstein and Contributors to Journal of Medicinal öheiiiistry, 8, 446 (1965) besohrieben. These derivatives have hypotensive activities.

The compounds to be produced according to the invention consist of Guanidine derivatives of the noradrenaline type, the hydroxyl groups of which are blocked in a heterocycle, such as the dioxol-1,3- and 1,4-dioxane cycles.

They are represented by the following formula

-Herein η is an integer from 1 to 3; m is equal to 0 or 1; X is hydrogen or halogen; R means hydrogen or a hydroxy Ire .st ·.

These guanidines can be according to the invention according to one of the produce the following methods that allow their recovery with be peaceful yields.

According to the first method, an amine base can be used in general formula

wherein X, R, m and η have the meanings given above react with a salt of S-alcohol isothiourea. The reaction is preferably carried out: with heat and in a solvent.

According to the second method, I leave the guanidines according to the Gain invention by condensation «ines salt of the above amine with cyanamide. When in the general formula

109808 / 213Ö

Z * means halogen, one can carry out a process that in the halogenation of a guanidine salt of the following formula

NH ^ NH,

preferably in a solvent such as acetic acid.

The free form guanidines can be easily obtained by treating the compounds obtained by the above methods

r. *

with a concentrated alkaline base over the addition salts the guanidines obtained with mineral or organic acids. These addition salts are new connections.

When in the general formula η = 2 or 3, m = 0 and R and X is hydrogen, the guanidines according to the invention from amines of the formula

wherein η s is 2 or 3. These amines receive themselves one from nitriles of the formula

where η = 2 or 3.

BATH ORIGINAL

109808/2138

According to the invention, the nitriles are made by splitting off water the corresponding aldoxime obtained, which itself by condensation of the corresponding Formy! benzodioxane or benzodioxepins with Hydroxylamine, obtained is one way of carrying out the invention acetic anhydride is used as a dehydrating agent Middle. The desired amines are obtained in a very good yield by reducing the nitriles. This reduction is preferably carried out using lithium aluminum hydride

The (amino-2 · ethanol-1 ^! ) -7- &ihydro-3> fc-EH-benzodioxepin-1,5 can be obtained according to the first method according to the invention by reducing the cyanohydrine of the formyl <»7-dihydx'o -3, ^ - 2H-benzodios: epins ~ 1, 5 or according to the second method from (Nitro-2 ⁴ -ethanol-1 ·) -7-dihydro-3,4-2H-Bensodio3: epiia-1,5 obtain.

The Guanidin® obtained according to the invention and their addition salts with mineral or © rgaad. see acids gallows remarkable hypptensiv® properties · The activities of these compounds are determined according to Terseiaiedaaen methods «First experiments were carried out on the analgesic rat, and the results are shown in columns 1, 2 and 3 of the following table. The arterial sleeve r®giet3? I © rt ms & d d ± ® effect of the product on the hypertension obtained by intravenous injection of noradrenaline w & A tyraein was carried out on the old urethane in euthanized rat © a mbm S> r @ iatravenös domestic product (previous) administered tand its effect em £ Al® Hyp @ @ rt®n i®n 'n examined that one with. N © rate © aalla (Ner) and Tyraein (Tyr) J received,

which themselves were given in © Stma & a late · v ©. The second In a series of experiments, the animals had been pretreated with the products to be tested on the evening before the experiment with the pressive Antoen.

109808/2130 BAD

These two test series make it possible to distinguish between the tf -blocking effects visible in the first test (columns 1 and 2) in the acute state and the more permanent effects of a sympathological nature that are visible during the pretreatment of the second test series (column 3) «

Then experiments were carried out on the anesthetized cat using the classic assembly of the flickering membrane and before and after intravenous injection of the product to be examined the concentrations recorded that were caused by irritation of the anesthetized fibers (column k of the table) «of the postganglionic fibers ( Column 5 of the table) and by adrenaline injection (column 5 of the table). At the same time the arterial tension was registered «

The experiments noted in column 7 of the table below have been carried out on lively cats, with the products being administered to lively cats by the subcutaneous route ©. While the days after the administration, the possible slackening of the flickering membrane was noted and the proportion of the eye covered estimated. ·

The toxicities of the tested compounds recorded in column 8 of the table are expressed as a lethal dose at 50 _% DL 50 in mg / kg of the products administered intravenously in mice. '

The table summarizes the result of this experiment.

Connect- » fertilize

V reach an anest & e rat

Codification of the Η — pertens effects τοπ Horadrenalin Tyraaiin Attempt · an iuia «ath ··. Kata · (fldjm «rnd · M ·· - b ran.)

Influence of intranOs ti of

Tersuch an dor

Connection Gate i.T. Verb.

1 hour · IP noradrenalin Tyraain aa pre- ¹ ^ connection- i " prevention evening mn" 1 2

R «iron« Adr · - P.

teren katae

DL 5 I.V. KlIu-

ml / k «

R-OHi n »1 j m» 1

RaH j n- 1

■ al; X> Br (in 6)

RaH {nat 2

PE3CNT0LJ.

(Mathan-

28

77

3 **

1**

53

80

0UAHETHI4. Pot.ntia-DtN li * i «r» nf «a 110 * ■ liojaJLr- lieailr- inji ~ fiber faser» iert h 5 6

Hh i> Pot «ndeicht · Light!« Ine inacti-r tiali- inhibi- Xnhibi · - Xadesierun »· rune runfung Nor. u.

Trr,

i> i? et- easily · borrowed no inactir tiali- inhibi- inhibi · - and · - sierunc rune rune rune

Npr,

Poten- Inhibier «Inhibier« keivenie 6k + tial. 100 1> 100 i> ne la- aktir 28 ________ Mor. dtrufi-

27 Poten- no · no · kei * · inactive 10 tial. Change "rune Iiiderune JS_d" -jse Ifor. u.

Inhibit. Inhi- Potoa- + no 100 ^ beer, tiali-Virkun_ 100 4 eggs «

29 Vote inhibitor. Imhi- Poten- Iati & li- 100 * beer, tiali ·. aktir 17 ,! eggs. 100 +

Nor · m. Trr.

no potea- iaak-

70 none none none inakkeine laderuae Indians · Indians, tir 25 Vd

kO < Potea- Zahibie- Inhi- Peten tialie. rune biorune tial. aktir 20 ver. ti. 100 i 100 *

109808 / 213Ö © OPY BAD ORIGINAL

1533924

From the consideration of this table, it follows that in the case of the plural represent compounds according to the invention a year or less strong Inhibi®ruia.g the HypsrtaRsiveffekt © dee Noradren & lina and TyraMim's acute test on rats occurs (columns 1 and 2). Bs is a syntpat © logical Sffakt darsalbea kind of like at dea of products known under the BessicJaau & g Phsntelaain are, g ^ Methanesulfonat v © a (H-p-Tolyl-Nia-Jiydroxyphenylaiaiaoäth.yl) -ijaidaaolinj · In certain connections it is necessary that 3icb. the ver & erga! 2.®nda ¥ irkang a syspatoflsgisclxQa effect of the same Art wis bsi dess under the Beseicliauag G-uanothidin knownθπ product (Octatoydroazocinyl-a-ailiiyl-i) ~ guanidine sulfate with inaböisoader © © imer "Verisin & arung der kontraktisrendan Sifskt © the heating of the front and postganglionärsn Fäs @ ra and dLa G-aganaatz Potantiertuag das koatraktisr ^ aden Effsktas of Adranaliainjiaierung at dsr Untarsuokua ^ superimposed on the flowing membrane of the anaesthetized body "

Mathyl-6-benzodioxane-1,4-graanidine possesses insbeaoadore iaTora of its Hesiisulfata "in a remarkable hypotensive" activity ₉ which has been investigated in humans "It has rarely been found that methyl-6-beazodioxane-1,4-guanidine sulfate is in TablattesiOra with a uniform content of clay 20 ssg aktivea Prinxip and aiaaai binding agent for oral yerabreichusig to overstretched patients 123. a daily adoais 20 - 40 mg oiH & a ragalssäßiga S®nkos & g dar Spannnag up to normal avorruft. Di® administration of zurai tablets as a day

Sick who have arterial hypertension, such as ^ asima of 22, Zk, 25

;; ■. allowed

^ and; Minima of 14, 11, 15 increased at the beginning of the treatment, / after •: 5-6 days of treatment to achieve ainar reduction in hypertension to maxima of 14 and JtLnima of 10 to 11 »t ■ · *. The clinical trial results show the effectiveness of guanidino-methyl-6-benzodioxane-1 _t k with the designation LH 433 in the form of his

109808/2138 bad original

- 8 hemisulphate to people.

First observation! Prau S. Bernadette »34 years. The patient shows an arterial hypertension maximum at 22, minimum at 14 at the start of treatment. The electrocardio diagram shows a free left ventricular hypertrophy »The kidney balance is normal; no Phenochromocytoma. After administration of two tablets LM 433 daily (one tablet in the morning and one tablet in the evening) with 20 mg of active substance, the tension drops regularly every day. On the sixth day of treatment, the arterial tension has a Maximum of 14 and a minimum of 10. Treatment is under Maintenance of the therapeutic gift continued

Second observation! Mrs. A. Anna, 3ό years. The patient possesses meningeal hemorrhage with arterial hypertension: maximum at 25 " Minimum at 15 and strong signs of left ventricular hypertrophy, possibly secondary hyperaldosteronism (malignant Kidney hypertension) and superimposed pyelonephritis. The patient is treated with LM 433) two tablets a day (one in the morning and one in the evening), adjusted to 20 mg and placed on a moderate salt-free diet (maximum 3g daily). On the fifth On the day of treatment, the hypertension had decreased «maximum at and minimum at 11. After discontinuation of treatment and maintenance a saltless diet and bed rest showed an increase in hypertension within five days of completing treatment, to a new maximum of 21 and a minimum of 13 reach. There were no signs of incompatibility with LM 433.

Third observation! Mrs. D. Adile, 65 years. The patient possesses a considerable left ventricular hypertension, tension a maximum of 24 and a minimum of 11 »application of a treatment with LM 433t two

109808/2138

Tablets daily (one in the morning and one in the evening) content each 20 ing led to a regular reduction in hypertension on the 5th day, which resulted in a level of 17 for maximum tension and, of 8 reached for the minimum voltage. The patient has the treatment very well tolerated and stands in its course without orthostatic Hypertension on.

Fourth observation: Mrs. S. Marie-Pauline, 61 years old “The patient is very obese and has arterial hypertension with heart failure due to permanent ear fibrillation. Its maximum tension reaches 18 and the minimum tension 9.5 «. A treatment with LM 433 * two tablets a day (one in the morning and one in the evening) of 20 mg leads to a reduction in arterial tension on the seventh day} maximum Ik and minimum 8. The treatment. is continued during the following days, with the therapeutic benefit being retained and secondary effects being absent.

The following examples illustrate the process according to the invention.

example 1

(Guanidino-a'-ethanol-1 ') _{-5-benzodioxole-1 f} 3-hemisulfate

^H 2 ^S0 4

CH - CH - - NH - C

NH

.1 / 2 H ₀ SO ₁ .

a) Q -Methylene-dioxy- 3 * fr-phenyl-fi-hydroxyethylamine This compound is obtained by reducing piperonylcyanhydrin with lithium aluminum hydride according to N. Adltyachaudhury (j. Ind. Chem. Soc. Volume 36, 1959, page 586) manufactured. The starting material is based on the method by FA Mason (J. Chem. Soc. London, Volume 119, "Beit" 1077).

1 OQdOd / 2138

The physical constants of ß-Methyien-dioxy-3,4-phenyl-ßhydroxyäthylamins are the following}

P = 75 ° C

0.07 ^Kp "■ ¹² ° - ¹²⁵ ° ^C · b) (guanidino-2'-ethanol-1 ') - 5-benzodioxol-1.3 hemisulfate

A solution of 1.66 g (0.012 mole) S-methylisothiourea hemisulfate in 10 ml of water with 2.17 g (0.012 mol) of ß-methylenedioxy-3,4-phenyl-ß-hydroxyethylamine prepared according to 1a), dissolved in 30 ml of ethanol. The mixture will last four hours heated under reflux, the methyl mercaptand vapors in a trap with a solution of sodium hydroxide and hydrogen peroxide catches. After heating, it is allowed to crystallize at ambient temperature. The (guanidino-2'-ethanol-1 ·) -5-benzodioxole-1,3-hemisulphate melts after suction and recrystallization from boiling water at 219 ° C (sample tube). The yield is 1.4 g.

Weight analysis C ^ H # N #

calculated 44.12 5.15 15.44 found 44.56 5.26 15.04

Example 2

(Guanidino-2'-ethyl) -5-benzodioxole-1,3-he'isulfate

^C 10 ^H 13 ^N 3 ° 2

A solution of 1.66 g (0.012 mol) of S-methylisothienaruetoffhe.mi- • ulfat in 10 μl Vasier will be bit 1.9 * llt after Max Er "· and Raeir ·" (S «lv · Ökiti. Aota,

10 08 0 8/2138

Volume 33 »1950. Page 914) dissolved in 20 ml of ethanol. The mixture is heated under reflux for four hours, during which the released methyl mercaptan is collected as in the previous example. “The solution is evaporated to dryness in vacuo and the residue obtained is crystallized in ethanol. Then iamkristallisiert from boiling water, and after extraction at ambient temperature is obtained in a yield of 40 * fo the (Z'-guanidino-ethyl) - 5-bensod.ioxol-1, 3-hemisulfate in the form of fine crystals, at 182 - Melting 183 ° C (sample tube) ο The concentration of the mother liquors allows homopiperonylamine sulfate to be recovered

Weight analysis

■ et H # N * calculated 46.87 5.47 16.41 found 46.89 5.67 16.36

Example 3 Guanidinomethyli-5-benzodioxole-1,3-hemisulfate

CH ₂ NH-C

a) Production of piperonylamine

Starting from piperonal, piperonylamine is obtained via the oxime, which leads to the corresponding nitrile by elimination of water, and this gives the desired amine by reduction by means of lithium aluminum hydride, piperonylamine is with a yield of 75 ^ obtained based on the output! Tril; Bp ^ = 86 ° C

U, O

(Mannich reports, volume 45, page 318 gives after reduction Sodium amalgam Kp. ". ■ I38 - 139 ° C).

IJ BD _ - -:

b) Guanidimethyl-5-benzodioxole-i.3-hemiaulphate

109808/213 Ö

BATH ORIGINAL

A mixture is heated under the conditions of Example 2 of 2.26 g (0.015 mol) of piperonylamine dissolved in 30 ml of ethanol and 2.08 g (0.015 mol) of S-methyl isothiourea hemisulfate, dissolved in 10 mm of water, four hours under reflux ο From the at ambient temperature A white crystalline solution is obtained if left to stand Compound after suction, washing with alcohol and crystallization melts from water at 242 to 243 ° C.

Weight analysis

C # H # N £

calcd 44.63 4.99 17.35 found 44.81 5, O4 17.25

example H

(Guanidino-2 ^t "-ethyl) -5-bromo-6 ~ ° benaodioxol-1,3-hydrobromide

- NH - C ^ BrH NH ₂

At ambient temperature, 2 g of (guanidino-2 ^l -ethyl) -5-benzodioxole-1,3-sulfate (0.00-8 mol), which were obtained according to Example 2, are dissolved in 25 ml of 80% acetic acid and added 1.4 g (0.0086 mol) of bromine in Poria of 25 ml of 80% acetic acid solution are added with stirring. When the addition is complete, place on a water bath for three hours, releasing hydrobromic acid. 3/4 of the solvent is then evaporated off in vacuo. It is suctioned off and recrystallized from ethyl alcohol. The product obtained is crystalline

■ 10 9 8 0 8/2136

lized in light resa platelets that melt at 21 ° C (sample tube)} yield «75 $ ·

Weight analysis Example 5 32,
32, H? 6 Br i 3.57
3.48 43.57
43.54 calculated
found b ► 73
, 71 ■
6-methylbenzodioxane-1,4-ieuanidine hemisulfate NH
N

- NH - D-NH ₂ , 1/2

a) Production of 6-methylamino-bonzodioxane-1.4

A) Xn a flask is added with stirring 25 g (0.152 Hol) 6-Forrnyl-benzodioxan-i, 4 (F ■ 50 ⁰ C Che ". Pharau Bull. Tokyo, i960, Volume 8, page 326) in 75 ml of ethanol and a lukewarm solution of 12.8 g (0.184 mol) of hydroxylaminoalorohydrate in 16 ml of water is added. Five minerals are stirred and a solution of 9.2 g (0.23 mol) of potassium hydroxide is then added. add in 15 »1 water. Stirring is continued for three hours at laboratory temperature. 80 g of crushed ice are then added and the solution is saturated

with carbon dioxide

After a soak in the refrigerator, the crystallized aldoxime is filtered off with suction, washed with water and dried. The raw product melts at 6Z - 63 "0, mach drying it becomes

109808/2138

used as such for the following manufacturing operations. The yield of crude product is 25 g, i.e. H. 91 #. After a Crystallization in water, the aldoxime is white and melts at 69 ° C (Koflerbank).

B) These 25 g of oxime dissolved in 30 ml of acetic anhydride are refluxed for 3 minutes. The solution is poured into 10Q ml of ice water, the precipitated 6-Nitrll-benzodioxane-1,4 is separated off by suction and then washed several times with ice water. After crystallization from boiling water, the nitrile melts at 108 ° C (Koflerbank) and has a boiling point below 0.55 millibars of 14 ° C. The nitrile yield is 77 $> based on the oxime.

Weight analysis C ₉ H ₇ NO ₂ M β 16 * 1.14 7 Yes yesterday Xi jf

calculated 67.10 4.38 8.69

found 67.30 4.43 8.76

TI ' in the fc. 16.1 g (0.1 mol) of nitrile, which was obtained after 5 »(B), are dissolved in 750 ml of ethanol and this solution is at a temperature below 0 ° C in a suspension of 4.5 β lithium aluminum hydride given in 100 ml of anhydrous ether. The mixture is heated under reflux of the ether on a water bath for three hours and then, while maintaining a temperature of 0 ° C., 9 ml of water, then 18 ml of 20% sodium hydroxide solution and finally 30 ml of water are added one after the other. These successive additions are made with vigorous stirring. While the ether is kept under reflux, stirring is continued for 45 minutes. Then the hydroxides are sucked off on a gas frit and washed several times with ether.

109808/2138

Fresh solutions are dried over Na_SOj. »The ether is evaporated and distilled under vacuum «The 6-aminomethylhenzodioxane-1,% distilled under 0.5 millibars at 102-103 ° C-. The yield

is 70>. , 16 C f Guaranteed βanalys e 65.48 C ₉ H ₁₁ HO ₂ M «165 calculated 65.39 found 1

H $ N #

6.70 8.47

, 6 ₈ 62 8.43

b). Preparation of 6 * -Methylbenaodioxan-1 »4-guajaidiahemisulfat Xn a flask equipped with stirrer and reflux condenser, 13.9 S (0.1 Hol) S-MethylisothionarnstoffheKisulfat, dissolved in 30 al water and sets a solution τοη 16.5 S (0.1 mol) 6-AMinomethylbenzodioxane-1,4 in 200 ml ethanol is added. During four hours of refluxing, a strong development of methyl mercaptane can be observed. A white precipitate is filtered off with suction which, after crystallization from boiling water and cooling to ambient temperature, crystallizes in form of fine white crystals which melt at 205 ° 0 (sample tube).

The binding of the action mother liquors to dryness provides one Residue, the something 6-Aminoaethylbenzodioxan-i, 4-eulfai; contains, the »an eliminated by three crystallizations from boiling water. A second harvest is obtained here, also at 205 ° C melts.

Weight analysis

C i> H ί Ν *

calcd 46.87 5.51 16.4O

found 46.77 5.42 16.25

109808/2138

Example 6

(2 »-Ethyl) -6-benzodioxane-1,4-guanidine hemioxalate

NH
CH. - CH - NH- C - NH-, 1/2 (COOH),

10.8 g (0.06 mol) (2'-ethylamino> - 6-benz odi oxane-1,5, Κρ _Λ _ «101 ° C, prepared according to the method of Masao Z © mita (Yakugaku Zasshi, 77, pp 2178-81, 1957), dissolved in 100 ml of ethanol, are mixed with a solution of 12.51 g (0.09 mol) of S-methylisothiourest of f-ee sulfate in 50 ml of water. The hybrid is refluxed for four hours The solution is then concentrated under vacuum until an oily residue is obtained, which is then dissolved in warm ethanol and left to crystallize at ambient temperature.

The crude product is crystallized twice from boiling water and consequently treated as below

As is brought into solution in cold water, it is made using n / 10 sodium hydroxide solution alkaline to displace the starting amine and extracted with three washes of chloroform. After evaporation of the In chloroform, 6-aminoethylbenzodioxane is obtained as hemisulfate; Kp ■ 208 - 210 ° C (sample tube) »

The aqueous solution freed from the amine is diluted with 10 figs of sodium hydroxide solution treated so that (2'-ethyl) -6-benzodioxane-1,4-guanidine as Base precipitates · It is extracted three times with chloroform and after drying the chloroform extracts over Na ^ SO ^ the solvent becomes

109808/2138

evaporated under vacuum on the water bath. The basic one is obtained Compound in the form of an oil insoluble in acetone. Then the Base treated with a 10 ^ strength acetone solution of oxalic acid, whereby the base is made immediately soluble. The acetone will evaporated in vacuo, the residue washed with Xfcher, among other things to remove excess oxalic acid! and the desired connection crystallized from a mixture of absolutea alcohol and ether.

The (2 ^f -äty ^ | -6-ben2odioxan-1,4-guanidinheaioxalat crystallizes in fine crystals; b.p. 238-240 ° 0 (sample tube)

Weight analysis

C ₁₁ H ₁₅ O ₂ M ₃ , 1/2 (COOH) ₂

Ο * H t V'jC

calculated 54.14 Πι, ΌίΓ "^ '15.78 found 54.02 6.22

Example 7

(2 * - £ thyl) -6-benzodi @ xan-1 A- i

In a flask, stir and heat on the metal bath 0.91 (θ.002 mol) (2 <-aainoethyl) -6-benaEodioxane sulfate and 0.25 g (0.006 moles) given Cyanaaid, dl «Teape

Minutes to 140-145 ° C and then further heated for one hour. The transparent resin formed is washed with acetone and extracted according to the method of Example 6 first with 10% sodium hydroxide solution and then with 10% sodium hydroxide solution · According to the conditions ύ . ·· Example 6 is treated with an oxalate solution and the desired compound is isolated.

Example 8

7 "-Methyl-dihydro-3" 4-2H-benzodioxepift- 1 r ^< Se * tiejiid ± MlieMietiH ⁱ at

109600/2138

OH ₂ -NH-C-HH ₂ , 1/2

^a ) Hearing of y -

Di ···· amine is derived from the corresponding 7-formyl compound, on which the aldoxia and then the nitrile are produced, since it is reduced

17.8c (0.1 mole) 7-Porayl-dihydre-3,4-2H-benzodioxepin-1,5 (Masao Tomita-Yakugaku Zasshi 77, 10 ^ 1-2-1957) are divided into 50 el Dissolved ethanol. 8.4 g (0.12 hol)

, dissolved in Yasser, added. Be will

Stirred for five minutes and while cooling old 6.05 C (0.15 mol) NaOH, dissolved in 10 al Yasser, added. The mixture is stirred for three hours at ambient temperature and a voluminous mixture is obtained. Lower base, t · β * into which 50 g of bis are added and a CO ₂ stream is passed in for two hours · Da · Aldoxlm is extracted with it with a yield τβη 93 £ · This compound is used in the raw state for the following work cycle .

18 g Aldoxia, dissolved in 30 al kealgic acid aahydride become 30 Maintained at reflux temperature for minutes. Kaoh of cooling the solution is added to 100 g of gestofion ·· bit, and the formed Nl «der» ohlag is sucked off, the naoh ümkriatallisatioii also a Mleokung of Bonsol and Hexa * at 82 ° 0 iehailat. Am· au · wara · »¥ ···· γ uakyiftallleiorto analysis sample is obtained

103808/2138

.. ■;. ■■ - 19 ■ - '.

in pearl-like lamellae which melt at 86 ° C (test tube).

The yield of 3 »^ - dihydro-2H-.foenssodioxepin.-1,5-nitrile-7 is 10.5 g, i.e. H. 64.5 ^.

CN

"XJ M. «175.18 H - / 7.99 ^C 10V ° 2 5 7.82 Weight analysis C. * 5 68, 55 .16 calculated 68, 68 , 17th found , 01

14 g (0.08 Hol) of this nitrile are dissolved in 100 μl of dioxane and added at 0 ° C. to a suspension of 3.8 g (0.08 mol) of lithium altrainium hydride in 250 ml of anhydrous ether. After this addition, the mixture is kept for three hours with stirring at ^ O ° _ÜL_ = ^ and then, after cooling on the ice bath, 10 ml of water, 10 oil, 20% sodium hydroxide solution and then 15 ml of water are added one after the other. The mixture is heated to 40 ° C. for one hour. The precipitate is filtered off with suction and the filtrate is evaporated and rectified. 56 μl of 7-AKlnomethyl «3,4-aihydr @ 2H-benzodioxepine> 1.5» bp ₀ g ^ j * ¹¹ ^ 12 ° G are obtained. The corresponding hydrochloride melts at 275 ° C (sample tube >) and sublimates towards 215 ° C.

Weight analysis 215 , 67 et H t C ₁₀ H ₁₃ MO ₂ , HCl M β Is «calculates 55.68 6, 5k found 55.59 6, 43 BATH ORIGINAL

6.36

109808/213 8

. - 20 -

b) Preparation of 7 ~ Metli3rl-3,4-dihydro-2H-benzodioxepine-1,5-guanidine hemiaulphate

3.6 g (0.02 mol) 7-aminoethyl-3,4-dihydro-2H-benzodioxepin - 1.5, dissolved in 30 ml of ethanol are refluxed for four hours with 2j8 g (0.02 mol) of S-methylisothioura hemisulfate in 15 ml Water heated · The solution is concentrated to half, and after After cooling, the white crystals formed are suctioned off, and 2.3 g analytically after two crystallizations from boiling water supply pure connection that melts at 220 to 222 ° C (sample tube)

Weight θanalyset Example 9 C + H # N $ C ₂₂ H ₃₂ NgOgS M ■ 540.89 48.89 5.97 15.54 48.78 6.14 15.41 calculated found 7- (2'-ethyl) -3.4-dihydro-2H-benzodioxepin-1 • ^ - ^ uanidine hemisulfate

.NH
CH ₂ - NH - S - NH ₂ , 1/2

3 »86 g (0.02 mol) 7- (2 ^l « ajainoethyl) -3,4-dlhydro-2H-benzodioxepine-15 (Maaao Teaiita, Yakugaku Zasehi 77, 104i - 1042, 1957 $ the author does not give the boiling point which was found to be 128 ° 0 below 0.6 millibars), dissolved in 20 ml of ethanol and 2.78 g (0.02 mol) of S-methylisothiourea, dissolved in 10 el of water, are kept at reflux temperature for four hours * After returning to Uitge-

1 Q 9 Ö 0 8/2138 BAD OBiQiHAL

A first yield of 1.8 g crystallizes at ambient temperature. To Aspirate the mother liquors with a volume of ethanol and then a volume of ether is added, which gives a second harvest of 2.2 g. After two recrystallizations from boiling water, 2.8 g are obtained shiny platelets in the sealed tube (Gallen Kamp device) two 223 ° C melts

Weight analysis set

^C 24 ^H 36 ^N 6 ° 8 ^{SM β} 568.64

G $ H $ N £

calculated 50.69 6.38 14th , 78 found 50.84 6.20 14th , 64 Example 10 7- (guanidine-2 • -ethanol-1 «) -3.4-dihvdro-2H-benzodioxeoin-1 j5-hemi- sulfate

NH

OH - OH ₂ - HH - 0 - HH ₂ , 1/2 OH

&) Production of 7- (Awin ^ o-2 ^> -ethanol »1 ') ~ 3.4» dihydro-2H ^ benzo »diexepJn-1.5 '
First method »

The 7-I'ormyl ~ 2,4'-dihydro-'2H-benzodio3Eepln-1,5-cyanohydrin, the subsequently is to be reduced, is produced in the following way

53.6 g (0.19 mol) of the bisulfite salt of 7-formyl-3,4-dihydro-2H-ben * odioxepla-1,5, dissolved in 110 ml of water, are given 55.9 g (1.14 Hol) iratrium cyanide, dissolved in 115 cm ^{3 of} water with stirring at a temperature of + 5 ° C. After the addition, the mixture is stirred for a further two hours at this temperature and then for one hour at 25 ° C. Raw cyanohydride extracted with ether is extracted i * rTvmt ~ ^ ij * AM ^ m * B ^

109808/2154

with a yield of # 89.

9.7 g (0.24 mol) LithiuaaluHiniunhydrid and 340 ml of anhydrous ether are at 10 ° C within 45 minutes 34.7 g (0.17 mol) of _t Cyanlnhydrins obtained above dissolved in 170 ml of ether, treated · After three Hours of stirring at ambient temperature and reflux for four hours. It is then cooled and, while maintaining the temperature at about 0 ° C., 34 ml of water, 54 ml of 20% sodium hydroxide solution and then 68 ml of water are added one after the other. The amine is extracted from this suspension with warm chloroform and, after drying, it is precipitated with hexane. The product obtained is filtered off and recrystallized from benzene · F "130 ° C ₀ 12 g yield. The boiling point of this amine below 0.5 millibar is 165 - 170 ° C

OH - CH - NH

OH

Weight analysis ⁰ I. calculated 1 ^H 15 ^NO 3 H * 209 , 24 N i found Oi H i 6th , 70 63.13 7, 23 6th , 72 63.03 7, 4o Second method

17.8 g (0.01 mole) 7-3

15 »2 g (0.25 mol) of nitromethane and 1/10 ml of methanol are added, while stirring at -8 ° C, with an oil of 2.3 M & lX ^ Tk) sodium in 80 ml of anhydrous methanol. After stirring for a further 5 minutes at -10 ° C., the pH is brought to approximately 5 with 18 g of beaige acid. Then let it stand for 5 hours at 0 ° O and the exhaust gas evaporates ; 0 <h% T vacuum, around 7- (nitro-2'-ftth 'oil-1)

2E-.fe »ss © ^ ixepin-1,5 au, which is dried with ether on top of atrium sulphate and then evaporation of the ether e *: ne Ulige terbiadung, which without purification "" it Lithium alufiiaie "hydride aaeh the first metaedine is redumed

TO ^ 006 / 2tυ

.Relctification one obtains 7-Jü8inoäihyl <-3,4-dih: Fdro-2H-benzoi-1,5 with a melting point of 130 C (BensBOl)

b) Horstel ^ u ^^ ') -3. 4-diJ aydro-2H- .

4 »1 @ g ,. (0 ₉ 02 mol) ania obtained according to a), dissolved in 42 al of ethanol and 2.78 g (0, Gg, mol) S-Metixylsotkioureaheeieulfat In 8 ml ¥ aes @ rw @ rd @ n four sttmcien burned to reflux temperature then the solution is allowed to crystallize after returning to ambient temperature and a yerbi damage is obtained. Recrystallization from boiling water at 230 - 232 ° C melts (sample tube)

Weight analysis? ■ _ ■

° 24 ^Η 3Λ ° 10 ^S. oi M « » 600 , 62 H * N $ 47, 99 6th , 04 14th , 00 calculated 48, 07 6th , 20 13th , 88 found

BATH

109808/2138

Claims (1)

1 · Process for the preparation of substituted guanidines of the general formula. CH - (CH.) - NH - NH NH. where η is an integer from 1 to 3 and m is «O or 1, X is water ·» substance or halogen and R is hydrogen or the hydroxyl group ι and ven their acidic addition salts, characterized in that that you have a basic amine of the general formula pH - (0Η ₂ ) _β -ΝΗ ₂ R wherein X, R ₁ and η have the meanings given above, with a salt of S-aleoylisothi © reacts urea or a salt of this amine with cyanamide or, if X in the guanidine is halogen, a salt of the guanidine of the following formula CH- (CH ₂ ) _b -MH-0 NH NH, preferably halogenated within a solvent » 2 «Method of manufacture. of compounds of the formula 109808/2138 in which a »is 2 or 3 and Y is a nitrile or methyl aino radical or vean η» 3 iet- hydroxyttthylaeino _t means that the production of a erfalire »n ^ oh. Claim 1 ₁ characterized in that the corresponding AldoxiM is dehydrated and then the nitrile obtained is reduced by means of LithluM-AluBiniuahydrld su de «AainderlTat. 109808 / 2t38